A variant of protein 3, the major transmembrane protein of the human erythrocyte, has been described (J. Biol. Chem., 252: 6573 (1977)). This variant has a 3,000 higher molecular weight than the normal polypeptide. The variation in the molecule is on the cytoplasmic surface of the membrane and the amino terminal end of the polypeptide. Preliminary screening has indicated that the variant occurs in 6% of a random population but a larger screening program will be undertaken. In order to expedite this program, an immunochemical assay for protein 3 and its variant will be developed. A study of the geographic distribution of the variant molecule is proposed. Special emphasis will be directed at a possible relationship between this variant and malaria. This relationship will also be explored in tissue culture studies of the malaria organism. At the molecular level, the variant portion of the protein 3 molecule will be defined by peptide mapping and amino acid sequencing. The relationship of protein 3 and variant to other membrane proteins and cytoplasmic proteins will be investigated using crosslinking agents. Since protein 3 is involved in facilitated anion transport protein, the relationship of the variant molecule to anion transport will also be investigated under a variety of experimental conditions.